Growth Factors Found in Breast Milk May Protect against Necrotizing Enterocolitis

Studies suggestthat ErbB4 receptor activation may be a novel therapeutic avenue for intestinaldiseases involving epithelial cell death, according to research published in TheAmerican Journal of Pathology

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Philadelphia, PA, September 9, 2014

Necrotizing enterocolitis (NEC) is a devastatinggastrointestinal illness affecting up to 10% of premature infants, with a 30%mortality rate, and formula feeding has been identified as a risk factor forNEC. A study published in The American Journal of Pathology foundthat growth factors present in human breast milk, but not in formula, mayexplain the protection against intestinal damage. Further, supplementing thediet of newborn NEC-affected rodents with these growth factors promotesepithelial cell survival.

"NEC is a highly morbid disease that can lead to multiplecomplications, including intestinal strictures, short gut syndrome, repeatedsurgeries, and extended hospital stays. Advances in understanding the growthfactor signaling cascades that maintain the healthy developing intestine couldlead to new methods for treating or preventing this devastating illness," saysMark R. Frey, PhD, The Saban Research Institute of Children's Hospital LosAngeles and the Keck School of Medicine of the University of SouthernCalifornia.

Driving this research is the quest to understand howhuman breast milk protects infants from NEC. Soluble growth factors found inbreast milk, such as epidermal growth factor (EGF) and heparin-binding EGF-likegrowth factor (HB-EGF), are thought to be possible protective molecules.Although both EGF and HB-EGF primarily activate the EGF receptor (EGFR), amember of the ErbB receptor tyrosine kinase family, HB-EGF also activates ErbB4receptors. "We have recently demonstrated that NRG4, an ErbB4-specific ligandthat does not bind or activate other family members, specifically promotessurvival but not migration or proliferation of mouse colon epithelial cells,"says Dr. Frey. Thus, NRG4 is a potentially unique and selective target for newtherapies.

Because there is no one experimental model thatreplicates human NEC, the investigators conducted a series of in vivo and in vitro experiments using different animal models as well asanalysis of human breast milk and intestinal tissue. The results all suggestthat NRG4-ErbB4 signaling may play a key role in protecting the developingintestine from inflammatory insults, says Dr. Frey.

Human NEC has been associated with the loss of Panethcells in the ileum. Paneth cells are found throughout the small intestine andare thought to be important components in the defense of gland stem cells frommicrobial damage. The investigators showed that NRG4 blocked Paneth cell lossin experimental mouse NEC. "This suggests that protection of Paneth cells orPaneth cell progenitors may be part of the mechanism of protection againstNEC," says Dr. Frey, though as yet the mechanisms by which ErbB4 could regulatePaneth cell survival are not well defined.

In final experiments, the researchers analyzed the wheyfractions of human milk from six anonymous donors, as well as formula controls,to see whether NRG4 is present normally in breast milk. Western blot analysisshowed that all six breast milk specimens were positive for NRG4, whereas NRG4was not detected in formula control samples. The authors also demonstrated thatErbB4 receptors were present in neonatal human small intestine, including samplesfrom infants who currently have or recently had NEC, supporting a functionalrole in the intestines.

This work was supported by National Institutesof Health grants R01DK095004(M.R.F.),K01DK077956 (M.R.F.), R03DK090295 (M.R.F.), K08DK083677(S.J.M.), R01AI014032 (H.R.F.), by a Senior Research Award from the Crohn's andColitis Foundation of America (M.R.F.), and a Research Career Development Awardfrom The Saban Research Institute (M.R.F.).

Full text of the articles is available to credentialedjournalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com.Journalists wishing to interview Dr. Mark R. Frey may contact himdirectly at +1 323 361 7204 or mfrey@chla.usc.edu.

About The American Journal of PathologyThe AmericanJournal of Pathology (http://ajp.amjpathol.org),official journal of the American Society for Investigative Pathology, seeks topublish high-quality, original papers on the cellular and molecular biology ofdisease. The editors accept manuscripts that advance basic and translationalknowledge of the pathogenesis, classification, diagnosis, and mechanisms ofdisease, without preference for a specific analytic method. High priority isgiven to studies on human disease and relevant experimental models usingcellular, molecular, animal, biological, chemical, and immunological approachesin conjunction with morphology.

The leadingglobal forum for reporting quality original research on cellular and molecularmechanisms of disease, The American Journal of Pathology is the most highly cited journal inPathology – over 39,000 cites in 2013 – with an Impact Factor of 4.602 andEigenfactor of 0.07076 according to the 2013Journal Citation Reports®, Thomson Reuters, and an h-index of206 according to the 2013 SCImagoJournal and Country Rank.

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